Agmatine prostaglandins

ABSTRACT

1. 1-AMINO-4-GUANIDOBUTANE 11A, 15(S)-DIHYDROXYL-9OXO-13-TRANS-PROSTENOATE.

United States Patent 3,845,111 AGMATINE PROS'IZAGLANDINS Alejandro Zaiiaroni, Atherton, Califi, assignor to ALZA Corporation No Drawing. Filed Sept. 16, 1970, Ser. No. 72,869 Int. Cl. C07c 87/00 US. Cl. 260-50144 18 Claims ABSTRACT OF THE DISCLOSURE Novel compounds of the formulae:

wherein R and R are hydrogen when Z is a single bond and when Z is a double bond R and R are absent; R is a keto,

H H 0H or 0R,

R is H or R5 is H,

H H H OH 11 or 01 Z is -CH CH or cis -CH =CH--; Z is a single bond or a double bond; Z is a single bond or a double bond when R; and R are hydrogen; 2.; is CH CH or trans -CH=CH; Z is -CH CH or cis -CH=CH; n is 2 to 5, m is 1 to 3, and x is 1 to 2. The compounds are useful for regulating blood pressure, for stimulating smooth muscles, for inhibiting gastric secretion and inhibiting platelet aggregation and they possess improved biological stability and enhanced membrane permeability to serve as an in vivo reservoir of the prostaglandin to ensure the biological availability of the prostaglandin.

BACKGROUND OF THE INVENTION The present invention concerns new and useful compounds related to the prostaglandins. More particularly, the invention pertains to novel 1,4-diaminobutane prostaglandin compounds and to novel 1-amino-4-guanidobutane prostaglandin compounds that possess enhanced biological stability, and the property to perform as a g gs-(cu and and

cn -z wn l -coo R R4 N tcfl umuz .z 3a-(cu -ZglH-Cih B B FORMULAB I wherein R and R are hydrogen when Z is a single covalent bond and R and R are absent when Z is a double covalent bond; 'R is a member selected from the group consisting of keto,

R is selected from the group consisting of hydrogen and R is selected from the group consisting of hydrogen,

R is hydrogen when Z is a single bond and it is absent when Z is a double bond; R is selected from the group consisting of OH and CR R is selected from the group consisting of hydrogen and hydroxyl; R is selected from the group consisting of acyl and alkoxyalkyl; R is selected from the group consisting of hydrogen and Z is selected from the group consisting of a saturated carbon carbon bond -CH CH and a cis unsaturated carbon carbon double bond CH=CH; Z is selected from the group consisting of a single bond or -a double bond; Z is a single bond except when R is hydrogen and R is hydrogen and R and R are hydrogen Z is a double bond; Z is selected from the group consisting of a saturated carbon carbon bond -CH CH and a trans unsaturated carbon carbon bond CH=CH; Z is selected from the group consisting of a saturated carbon carbon bond -CH CH and a cis unsaturated car bon carbon bond CH=CH; and wherein n is 2 to 5 m is 1 to 3 and x is 1 to 2. The wavy line in the formula indicates the stereochemistry of the attached group on the cyclopentyl ring or on the side chain and it indicates either an on or ,8 configuration. The dotted line indicates that the attached group are a oriented or on the same side of the cyclopentyl ring as the carboxyl side chain and a wedged line indicates that the B-sustituents are oriented on the same side of the ring as the alkyl side chain. The wavy line on the alkyl side chain indicates that the attached group may have a configuration represented by the terms sinister (S) and rectus (R) which for these compounds are equivalent nomenclature of IX, and 5 respectively.

The novel and the unobvious putrescine prostaglandins and agmatine prostaglandins of the invention as embraced by Formulae l are primarily related to the prostaglandins, a family of naturally occurring endogenous biologically important compounds possessing diverse and valuable pharmacological properties. The prostaglandins, a family of lipid acids are generally characterized as being carbon atom prostanoic derivatives and they are usually separated into categories such as prostaglandin E, F, A and B. The separation of the prostaglandins depends on the arrangements of double bonds, hydroxyl and ketone groups, for example the E-type prostaglandin-s have an lla-hydroxyl group and a 9-keto group in the five-me-mbered cyclopentyl ring while in the F-type prostaglandins the 9-position is substituted with an a-hydroxyl group and the compound still retains the ll-hydroxyl group. The A-type and B-type prostaglandins do not have the familiar ll-hydroxyl group that is present in the Es and ES. The prostaglandins are also classified as primary, secondary and tertiary depending on the number of double bonds present in the prostaglandin. For example, the primary prostaglandins containing a 13:14 double bond are called E and F The prostaglandins that contain an additional double bond at the 5:6 position are designated as E and F and the prostaglandins with an added third double bond positioned at 17: 18 are termed E and F respectively with the classification also used for the various categories.

The valuable physiological properties known by the art to be possessed by the prostaglandin family includes the prostaglandin ability to stimulate or control alimentary and reproductive smooth muscles, the ability to block gastric acid and enzyme secretions by the stomach, the property to stimulate the synthesis of adrenal corticoids, and to aid in regulating blood pressure, their possible role as "a mediator of hormonal functions, and their ability to inhibit platelet aggregation. While the family as a group possesses these actions, the actions of each of the E, F, A and B prostaglandins are often dissimilar and sometimes they are opposed. For example, the prostaglandins of the E-type configuration are vasodepressors and they decrease the motility of the uterus at ovulation while the prostaglandins of the F-type usually have the opposite efiects. The E-prostaglandins also inhibit platelet aggregation while the F-prostaglandins are devoid of this property. The prostaglandins of the A-type structure are like the E-type with respect to their vascular smooth muscle action but they possess a difiering degree of relative potency as gastrointestinal secretion regulating agents.

Even though the prostaglandins are known to possess the above mentioned valuable pharmacological utilities in vitro that could be selectively used by various glands, tissues and org-ans, the potential pharmaceutical utilization of these compounds has not been presently realized in vivo because the prostaglandins lack the necessary biological stability that lends itself to therapeutic application of the prostaglandins. For example, the prostaglandins of the art known biologically active E-type chemical structure in the presence of acidic conditions readily change to prostaglandins of the Atype structure that possess different biologic-a1 activities, and the A-type prostaglandin under prolonged exposure to biological gastric acidic conditions isomerize to B-type prostaglandins. The prostaglandins that are known by the art to evidence widely diiferent biological activities which 'make their physiological application seemingly more difiicult and sometimes unpredictable in the face of these possible in vivo changes in chemical structure and physiological ac tivities. These changes also lessen the availability of useful prostaglandin for in vivo use by changing useful prostaglandins that can be absorbed from the vascular system to inactive metabolic forms of the prostaglandin-s.

In the light of the above presentation, it will be easily appreciated by those versed in the art that a need exists for increasing the biological stability of the family of prostaglandins while essentially maintaining and readily making available to biological receptors the physiologically useful prostaglandins. It will also be appreciated that a need exists for providing new prostaglandin compounds that can serve as a reservoir of the prostaglandin per se for vascular circulation and subsequent avail-ability by release of the prostaglandin from the prostaglandin compound to cells, glands and tissues for their immediate physiological use while simultaneously increasing the biological stability of the prostaglandin.

Accordingly, it is an immediate object of the present invention to make available to the art novel and unobvious prostaglandin compounds that overcome the problems often associated with the prior art.

Yet another object of the present invention is to provide new prostaglandin compounds that possess enhanced biological stability against rapid metabolism to ensure their in vivo employment for their known pharamcological properties.

Still yet another purpose of the subject invention is to provide prostaglandin compounds that can act as both an intracellular and extracellular biological reservior of the prostaglandin for circulating within the vascular system to ensure increased availability as needed by the cells, glands and tissues for their immediate use.

Yet still another object of the invention is to provide prostaglandin compounds that possess enhanced cell membrane permeability in certain hosts for intracellular prostaglandin performance.

Another object of the invention is to provide new 4- (aminobutyl) guanidine prostaglandins and 1,4-diaminobutane prostaglandins that possess useful properties for both in vivo and in vitro applications.

These and other features, objects and advantages of the present invention will become pore readily apparent from the following detailed description of the invention taken in conjunction with the accompanying claims.

SUMMARY OF THE INVENTION The present invention concerns novel 4-(aminobutyl)- guanidine prostaglandins and 1,4 diaminobutane prostaglandins that are characterized by unobvious and desirable biological properties such as improved biologcal stability, the property of the 4-(aminobutyl)-guanidine prostaglandins on the 1,4-diarninobutane prostaglandins to circulate within the vascular system as a biological reservoir for a continual source of the prostaglandin moiety of the novel compounds at the needed biological prostaglandin receptive site following the release of the prostaglandin moiety from the compound, and also by an enhanced membrane permeability for absorption through the biological membranes.

DESCRIPTION OF THE INVENTION The novel 4-(aminobutyl)-guanidine prostaglandins and 1,4-diaminobutane prostaglandins of the invention as illustrated by Formulae I are prepared by contacting and reacting a prostaglandin of Formulae II:

FORMULAE II wherein R and R are hydrogen when Z is a single bond and R and R are absent when Z is a double bond; R

R, is hydrogen,

H H H H OH on.

R-, is hydroxy or 0R R is hydrogen or hydroxy; R is an acyl derived from a carboxylic acid or an a-alkoxyalkyl; Z is a saturated carbon carbon bond CH CH or a cis unsaturated carbon carbon bond -CH=CH; Z is a single bond or a double bond; Z is a single bond except when R, is hydrogen and R is hydrogen and when R, and R are hydrogen Z is a double bond; 2., is a saturated carbon carbon bond CH CH or a trans unsaturated carbon carbon bond CH=CH; Z is a saturated carbon carbon bond -CH CH or a cis unsaturated CH=CH; n is 2 to 5; m is 1 to 3.

The wavy line in the formula indicates the stereochemistry of the attached substituents on the cycloalkyl ring or on the side chain may have either an a or a p configuration. The dotted line indicates that the attached groups are u-oriented or on the same side of the cyclopentyl ring or the carboxyl side chain and the wedged line indicates that the ,B-substituents are oriented on the same side of the ring as the alkyl side chain. The wavy line on the alkyl side chain indicates that the attached groups may have a configuration represented by the terms sinister (S) and rectus (R) which for these compounds are equivalent nomenclature of a and 3 respectively; with a compound of Formula III:

wherein R is selected from the group consisting of The reaction of the prostaglandins of Formulae II with either the 1,4 diaminobutane or the 4 (aminobutyl) guanidine of Formula III for preparing the corresponding prostaglandin compound of Formulae I is carried out in the presence of a suitable inert solvent with mixing of stoichiometric amounts of the reactants at room temperature or in a warmed solvent and gradually mixing the reacting ingredients until all the ingredients are in solution. The novel 1,4 diaminobutane prostaglandin or the 4- (aminobutyl) guanidine product is obtained by chilling the resulting mixture to precipitate the crystals, powder or the product that can be isolated by the addition of a miscible diluent of low polarity or by standard evaporation techniques. The obtained crystals or powders are filtered, washed and dried, usually in a desiccator over a known drying agent to a constant weight.

The starting materials used herein to synthesize the novel compounds of Formulae I are prepared in known ways or they are readily obtained from commercial sources. The reacting materials of Formulae II are easily prepared in art known ways either by isolating the prostaglandin from natural sources, for example, the vesicular glands of sheep, or by the enzymatic conversion from fatty acid substrates such as arachidonic acid, and depending on the substituents desired, routinely chemically transforming double bonds to single bonds by hydrogenation, converting keto groups to hydroxymethylene groups by reduction, by dehydrating to introduce double bonds, by forming carbinol derivatives by treating a carbo (lower) alkoxy group with an alkali metal alumino hydride reducing agent such as lithium aluminum hydride and the like. Specific prior art methods that set forth the procedures useful to provide all of the compounds of Formulae II are found in Science, Vol. 158, pages 382 to 391, 1967; Recueil, Vol. 85, pages 1233 to 1250, 1966; Biochem'. Biophys. Acta., Vol. 106, pages 215 to 217, 1965, Agnew. Chem. Inter. Ed., Vol. 4, pages 410 to 416, 1965; Experientia, Vol. 21, pages 113 to 176, 1965; Recueil, Vol. 85, pages 1251 to 1253, 1966 and other art recorded procedures.

The prostaglandin compounds depicted by Formulae II can also be chemically synthesized by well-known methods, for example, from 2-oxobicyclo-(3.3.0)-oct-6-en-3- one as described in Tetrahedron Letters, Vol. 4, pages 311 to 313, 1970; by the hydrogenation of ll,l5-bis(tetrahydropyranyl) ether of 9a,1loz,15 (S) -trihydroxy-5-cis,13- trans-prostadienoic acid over Pd/ C followed by hydrolysis and treatment with Jones reagent to give the resulting prostaglandin as reported in J. Am. Chem. Soc., Vol. 92, pages 2586 to 2587, 1970; by the acid-catalyzed opening and rearrangement of epoxybicyclo (3.1.0)-hexane as described in J. Am. Chem. Soc., Vol. 91, pages 5364 to 5371, 1969; by the reduction of 9-oxo and 15-oxo prostaglandin derivatives to give the R and S isomers of the corresponding hydroxyls and the dehydration of ll-hydroxy-9-oxoprostanoic acid to :give the ketones as recorded in J. Org. Chem., Vol. 34, pages 3552 to 3557, 1969; and J. Lipid Research, Vol. 10, pages 320-325, 1969; as prepared by reduction of 2-oxo-3-oxo-6-exo-(trans-3- (S)hydroxy-hept- 1 enyl)-endo-7-acetoxy-cis-bicyclo(3.3.0)octane followed by reduction and treatment with Wittig reagent to give the corresponding prostaglandin as in J. Am. Chem. Soc., Vol. 91, pages 5675 to 5677, 1969; and other reported chemical synthesis embracing compounds within Formulae II such as J. Am. Chem. Soc., Vol. 92, pages 937 to 938, 1970; J. Am. Chem. Soc., Vol. 91, pages 5675 to 5677, 1969; Tetrahedron Letters, Vol. 5, pages 465 to 470, 1966; The Proceedings of the Robert A. Welch Foundation Conference on Chemical Research, Vol. XII, pages 51 to 79, 1969; Chem. Abst., Vol. 66, page 75770; and T etrahedron Letters, No. 59, pages 5185-5188, 1969.

Representative of the alkanoyl moieties are the alkanoyl groups containing 1 to 18 carbon atoms such as formyl, acetyl, propionyl, butyryl, isovaleryl, valeryl, hexanoyl, caproyl, octanoyl, heptanoyl, lauroyl, palmitoyl, stearoyl,

nonanyl, oleoyl and the like. Exemplary of ovalkoxyalkyl groups embraced with R is the group wherein R is an alkyl group of 1 to 7 carbon atoms inclusive, such as the straight or branched chain alkyl groups methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, pentyl, neopentyl, n-hexyl, isohexyl and the like. The group R is hydrogen or the lower alkyls of 1 to 7 carbon atoms as just set forth.

Compounds that are suitable for the purpose of the invention that are represented 'by Formulae II with their usual names based on art recognized prostanoic acid nomenclature and followed by the presently used abbreviations are the compounds 1 111,1 (S -dihydroxy-9-oxo- 13-trans-prostenoic acid(PGE 115,15 (R)-dihydroxy-9-oxo-13-trans-prostenoic acid,

(1l,15-epi-PGE its antipodes, ent-l1,15-epi-PGE 11a,15 (S)-dihydroxy-9-oxo-5-cis,13-trans-prostadienoic acid, (PGE 1 1a, 15 (S)-dihydroxy-9-oxo-5-cis,13-trans,17-cisprostatrienoic acid, (PGE 15 (S)-hydroxy-9-oxo-13,13-trans-prostadienoic acid,

15 (S)-hydroxy-9-oxo-5-cis,10,13-trans-prostatrienoic acid, (PGA 9051 104,15 (S) -trihydroxyl 3-trans-prostenoic acid,

9,8,1 111,15 (S) -trihydroxy-13-trans-prostenoic acid,

9,6,1 1 6,15 (R)-trihydroxy-13-trans-prostenoic acid,

(11,15-epi-PGF its antipode, ent-11,15-epi-PGF 9a,1 :,15 (S) -trihydroxy-5-cis,13-trans-prostadienoic acid, (PGF 9p,11a,15(S)-trihydroxy-5-'vis,13-trans-prostadienoic acid, (PG'F 911,1 10:,15 (S)-trihydroxy-5-cis,13-trans, 17-cis-prostatrienoic acid, (PGF 9,3,11a,15(S)-trihydroxy-5-cis,13-trans-17-cis-prostatrienoic acid, (PGF (S)-hydroxy-9-oxo-8 12) ,13-trans-prostadienoic acid, (PGB v 15 (S -hydroxy-9-oxo-5-cis,8 12 1 S-trans-prostatrienoic acid, (PGB 15 (S), 19-dihydroxy-9-oxo-8( 12),13-trans-prostadienoic acid, (19-hydroxy PGB 15 (S) 19-hydroxy-9-oxo-10, 13 -trans-prostadienoic acid,

(19-hydroxy PGA 15 (S -hydroxy-9-oxo-8 12 -prostanoic acid, (dihydro PGB and the like.

The starting material of Formula III, 1,4-diaminobutane, also known as tetramethylene diamine and putrescine, is a naturally occurring product formed certain mammals on the decarboxylation of the amino acid ornithine by the enzyme ornithine decarboxylase. The compound is commercially available and it can also be synthesized according to the procedure of Japanese Pat. No. 158,357 by the ammonolysis of a saturated straight chain hydrocarbon dibromide in the presence of an aluminum catalyst to give the correspondingstraight chain hydrocarbon diamine. The compound, 1,4'-diaminobutane can also be prepared by the hydrogenation of 1,2-dicyanoethylene using a cobalt catalyst and ammonia as described in British Pat. No. 576,015. Other known procedures for the preparation of 1,4-diaminobutane include the benzoylation of a halobutylamine and then converting the monobenzoylhalobutylamine with ammonia to the diaminobutane as in Biochem. J., Vol. 19, pages 845 to 849, 1925; and by the procedure in Arch. of Biochem. and Biophys., Vol. 79, pages 338 to 354, 1959.

The starting material of Formula III, 1-amino-4-guanidobutane, also known as 4-(aminobutyl)-guanidine and agmatine, occurs naturally in ergot, sponges and herring sperm and in certain mammals resulting from the decarboxylation of the exogenous essential amino acid arginine, a-amino-guanidinovaleric acid. Agmatine is commercially available and it can be synthesized from tetramethylenediamine by reacting it with silver cyanamide according to the procedure in Z. Physiol. Chem., Vol. 68, pages 170 to 172, 1910; ibid, Vol. 118, pages 277 to 283, 1922. Agmatine can also be made by the H NCN H NC(:NH)SCH process of J. Chem. Soc. Japan, Vol. 67, pages 132 to 133, 1946; and Ber., Vol. 90, pages 1251 to 1258, 1957. The starting reactants of Formulae II and Formula III used to synthesize the compounds of Formulae I are known to the art and these starting reactants are not part of the present invention.

The solventssuitable for the purposes of the present invention include the more polar type of solvents such as tetrahydrofuran, chloroform, acetone, methylene chloride, ethylene chloride, dioxane, isobutyl ketone, methyl isobutyl ketone, dimethyl ether, diethyl ether, alkanols such as methanol, methyl butanol, n-amyl alcohol, 2-ethyl hexyl alcohol, ethylene glycol, ethanol, isopropanol, hexanol, butanol, pentanol and lesser polar solvents such as benzene, carbon tetrachloride, cycloalkanes such as cyclopentane, 1,Z-dimethylcyclopentane, cyclooctane, isopropylcyclohexane, cyclohexane, and methylcyclohexane; alkanes such as 3-methylpentane, n-hexane, n-heptane and the like.

The following examples are given simply to illustrate this invention, but they are not in any way to be construed as limiting the scope of the invention as these and other means for performing the invention will be obvious to those versed in the art in the light of this disclosure.

EXAMPLE 1 To a room temperature solution of 11a,l5(S)-dihydroxy-9-oxo-13-trans-prostenoic acid (0.355 gram, 0.001 mole) in millilters of dry methylene chloride there is added 0.130 gram, 0.001 mole of 1-amino-4-guanidobutane. The mixture is heated to about 35 C. and cooled to room temperature. Then, 100 milliliters of petroleum ether is added and the resulting mixture is chilled in an ice bath. The solids are filtered, washed with more petroleum ether and suspended in warm dry petroleum ether. Petroleum ether is added until turbidity develops and the mixture is chilled overnight. The crystals are filtered, washed with petroleum ether and dried in a desiccator over concentrated sulfuric acid to a constant weight, to give the novel compound 1-amino-4-guanidobutane '15 (S) -dihydroxy-9-oxo-13-trans-prostenoate.

EXAMPLE 2 To a room temperature 30 ml. solution of ethanol containing 0.352 gram, 0.001 mole of 11a,l5(S)-dihydroxy- 9-oxo-5-cis-13-trans-prostadienoic acid is added with constant stirring a 30 ml. of warmed, methanol solution of 0.130 gram, 0.001 mole of 1-amino-4-guanidobutane. Next, the solution is evaporated under vacuum and the resulting product is triturated with ether-benzene mixtures and the product 1-amino-4-guanidobutane 11a,15(S)-d1 hydroxy-9-oxo-5-cis-13-trans-prostadienoate is dried in a desiccator over concentrated sulfuric acid.

EXAMPLE 3 The procedure of Example 2 is employed in this example by reacting stoichiometrically equivalent amounts of 9a,1101,15(S)-trihydroxy-13-trans-prostenoic acid with 1- amino-4-guanidobutane in methylene chloride with constant stirring at room temperature. After the solution is evaporated under light in-house vacuum, the product 1- amino-4-guanidobutane 9a,11oc,15(S) tri hydroxy 13- trans-prostenoate is triturated with dry cyclohexane and the product is filtered, washed with benzene; and, finally it is dried in a desiccator over concentrated sulfuric acid to a constant weight.

EXAMPLE 4 The synthesis of 1 amino 4 guanidobutane 9a,11a, 15 (S)'trihydroxy-5-cis,13-trans-prostadienoate is carried out by first adding to a room temperature 50 ml. tetrahydrofuran solution containing 0.708 gram, 0.002 mole of 901,11a,15(S)-trihydroxy--cis 13 trans-prostadienoic acid to a 50 ml. tetrahydrofuran solution containing 0.260 gram, 0.002 mole of 1-amino-4-guanidobutane with constant stirring until the mixing of the two solutions is complete. Next, the mixed solution is warmed to about 50 C. to 55 C. for /2 to hours to ensure essentially complete formation of the desired product. Then, the solution is cooled to room temperature and the solvent evaporated with the resulting product triturated with dry benzene. Finally, the product is filtered, washed with a little benzene and dried in a vacuum desiccator to constant weight.

EXAMPLE 5 Preparation of 1,4-diaminobutane 1la,15(S)-dihydroxy- 9-oxo-13-trans-prostenoate: To a room temperature solution of 0.355 gram of 1111,15(S)-dihydroxy-9-oxo-l3- trans-prostenoic acid in 100 ml. of dry ethylacetate is added 0.088 gram of 1,4-diaminobutane in 100 ml. of dry benzene. Then, 0.2 liter of petroleum ether is added and the resulting mixture is chilled and the formed solids are filtered, washed with petroleum ether and suspended in warm dry benzene. Petroleum ether is again added until turbidity develops and the mixture is chilled overnight. The crystals are filtered, washed with petroleum ether and dried in a desiccator over concentrated sulfuric acid to a constant weight.

EXAMPLE 6 The synthesis of 1,4-diaminobutane biS-(9oc,11m,15(S)- trihydroxy-13-trans-prostenoate) is carried out by first adding to a room temperature 50 m1. tetrahydrofuran solution containing 0.712 gram, 0.002 mole of 9a,11ot,15(S)- trihydroxy-13-trans-prostenoic a 50 ml. tetrahydrofuran solution containing 0.088 gram, 0.001 mole of 1,4-diaminobutane with constant stirring until the mixture of the two solutions is complete. Next, the mixed solution is warmed to about 50 C. to 55 C. for /2 to 1- /2 hours to assure essentially complete formation of the desired product. Then, the solution is cooled to room temperature and the solvent evaporated with the resulting product triturated with mixtures of benzene petroleum ether. Finally, the product is filtered, washed with a little benzene and dried in a vacuum desiccator to a constant weight.

EXAMPLE 7 The compound 1,4-diaminobutane biS(9a,l1oc,15(S)- trihydroxy-S-cis-l3-trans-prostadienoate) is prepared by mixing 0.706 gram, 0.002 mole of 9a,11u,15(S)-trihydroxy-S-cis-13-trans-prostadienoic acid in 50 ml. of dioxane with 0.088 gram, 0.001 mole of 1,4-diaminobutane in 50 ml. of dioxane at room temperature. Next, the solution is heated to about 45 C. to 50 C. to assure the formation of the ionic compound 1,4-diaminobutane bis- (9a,1la,15(S)-trihydroxy 5 cis,13-trans-prostadienoate). Finally, the solvent is evaporated and the product triturated with benzene. The product is filtered, washed with a little benzene and dried in a vacuum desiccator to a constant weight.

EXAMPLE 8' The compound l-amino 4 guanidobutane-bis-(lla, (S)dihydroxy 9 oxo 13-trans,protenoate) is prepared by contacting and reacting (0.710 gram, 0.002 mole) of 11u,15(S) dihydroxy 9 oxo-13-trans,prostenoic acid in 50 ml. of dioxane with 0.130, gram, 0.001 mole of 1-arnino-4-guanidobutane in 50 ml. of dioxane at room temperature. Next, the solution containing the two reactants is heated to about 45 C. to 50 C. to assure the formation of the ionic compound l-amino-4-guanidobutane bis-(l1u,15(S)-dihydroxy 9 oxo-13-trans,prostenoate). Finally, the solvent is evaporated and the product triturated with benzene. The product obtained is filtered, washed with a little benzene and dried in a vacuum desiccator to a constant weight.

Other novel compounds that are readily prepared according to the manner of the invention are for example,

1-amino-4-guanidobutane 1 10c, 15 (S -dihydroxy9-oxo- 5 -cis, 1 3-trans, 17 -cis-prostatrienoate;

1-amino-4-guanidobutane 15 (S) -hydroxy-9-oxo-10, 13-

trans-prostadienoate;

1-amino-4-guanidobutane 15 (S -hydroxy-9-oxo-5-cis,

10,13-trans-prostatrienoate;

1-amino-4-guanidobutane 9,8,11a,15(S)-trihydroxy-13- trans-prostenoate;

1-amino-4-guanidobutane 913,1 1oc,15 (S) -trihydroxy-5- cis, l 3-transprostadienoate;

1-amino-4-guanidobutane 901,1 111,15 (S) -trihydroxy- 5-cis,13-trans, 17-cis-prostatrienoate;

1-amino-4-guanidobutane 9B,11a,15(S)trihydroxy-5- cis,13-trans-l7-cis-prostatrienoate;

1-amino-4-guanidobutane 15 (S -hydroxy-9-ox0-8 l 2) 13-trans-prostadienoate;

1-amino-4-guanidobutane 15 (S) -hydroxy-9-oxo-5- cis,8 l2) ,l3-trans-prostatrienoate;

l-amino-4-guanidobutane 15 (S) ,19-dihydroxy-9-oxo 8 12) ,1 3-trans-prostadienoate;

1-amino-4-guanidobutane 15 (S) 1 9-dihydroxy-9-oxo- 10,13-trans-prostadienoate;

1-amino-4-gu anidobutane 11a, 1 5 (S) -dihydroxy-9- oxo-prostano ate;

1-amino-4-guanidobutane 15 (S -hydroxy-9-oxo-8 12 prostanoate;

1,4-diaminobutane 1 10:,15 (S -dihydroxy-9-oxo-5-cis,

13-trans-prostadienoate;

1,4-diaminobutane 1105,15 (S) -dihydroxy-9-oxo-S-cis,

13-trans, l7-cis-prostatrieuoate;

1,4-diaminobutane 15 (S) -hydroxy-9-oxo-10,l3-transprostadienoate;

1,4-diaminobutane 15 (S) -hydroxy-9-oxo-5-cis,10,13-

trans-prostatrienoate;

1,4-diaminobutane 9a,11a,15(S)-trihydroxy-13-transprostenoate;

1,4-diaminobutane 9 8,1 10:,15 (S) -trihydroxy-l3-transprostenoate;

1,4-diaminobutane 9oz, 1 1:115 (S) -trihydroxy-5-cis, 1 3- trans-prostadienoate;

1,4-diamin0butane 9a, 1 111,15 (S) -trihydroxy-5-cis, l 3- trans,17-cis-prostatrienoate;

1,4-diaminobutane 9 8,1 1a,15(8)-trihydroxy-5-cis,13

transl7-cis-prostatrienoic;

1,4-diaminobutane 15 (S) -hydr0xy-9-oxo-8( 12),]3-

trans-prostadienoate;

1,4-diaminobutane 15 (S) 19-dihydroxy-9-oxo-10, 1 3- trans-prostadienoate;

1,4-diaminobutane-bis-( 1 101,15 (S -dihydroxy-9-oxo 13-trans-prostenoate) 1,4-diaminobutane-bis-( 1 la, 15 (S) -dihydroxy-9-oxo-5- cis, l 3-trans-prostadienoate;

1,4-diaminobutane bis-( 1 l a, 15 (S) -dihydroxy-9-oxo-5- cis,13-trans,17-cis-prostatrienoate;

1,4-diaminobutane bis-(9,8,1 104,15 (S -trihydroxy-5-cis,

13-trans-prostadienoate;

1,4-diaminobutane biS-(9cx,11oc,15 (S -trihydroxy-5- cis,13-trans, l7-cis-prostatrienoate) 1,4-diaminobutane bis-(9 8, 1 104,15 (S) -trihydroxy-5-cis,

13-transl7-cis-prostatrienoate) 1,4-diaminobutane bis-( 15 (S) ,19-dihydroxy-9-oxo- 8(l2),13-trans-prostadienoate and the like.

This invention resides in making available to the art the novel above described 1,4-diaminobutane prostaglandin compounds and 1-amino-4-guanidobutane prostaglandin compounds that are presently believed to possess unobvious and improved properties not suggested by the prior art such as enhanced stability towards biological conditions, the ability to act as an in vitro reservoir and thereby to serve as a source of prostaglandin per se when the 1,4-diaminobutane prostaglandins and 1-amino-4- guanidobutane prostaglandins are circulated by the vascular system to prostaglandin receptive sites in tissues, cells and the like, when in contact with the cellular membranes integral with the glands, tissues and cells, they may enter into the cell for subsequent metabolic hydrolysis of the novel 1,4-diaminobutane prostaglandin or 1- amino-4-guanidobutane to make available as the needed biological site prostaglandin per se. In addition, the compounds possess valuable properties that make them important for laboratory studies with laboratory animals because of their enhanced capillary permeability which makes possible topical absorption studies, cellular diffusion experiments, and the like.

The novel compounds of the invention can be used by the pharmaceutical and the veterinary arts in a variety of pharmaceutical preparations or veterinary preparations. In these preparations, the new compounds are administrable in the form of tablets, pills, powders, capsules, injectables, solutions, suppositories, emulsions, dispersions, food premix and in other suitable forms. The pharmaceutical or veterinary preparation which contains the compound is conveniently admixed with a non-toxic pharmaceutical organic carrier or a non-toxic pharmaceutical inorganic carrier. Typical of pharmaceutically acceptable carriers, are for example, water, gelatine, lactose, starches, magnesium stearate, talc, vegetable oils, polyalkylene glycols, petroleum jelly and other conventionally employed pharmaceutically acceptable carrier. The pharmaceutical preparation may also contain non-toxic auxiliary substances such as emulsifying, preserving, wetting agents and the like, as for example sorbitan monolaurate, triethanolamine oleate, polyoxyethylene sorbitan monopalmityl, dioctyl sodium sulfosuccinate, and the like.

Exemplary of a typical method for preparing a tablet containing the active ingredient is to first suitably comminute the active ingredient with a diluent such as starch, sucrose, kaolin or the like to form a powder mixture. Next, the just prepared mixture can be granulated by wetting with a non-toxic binder such as a solution of gelatin, acacia mucilage, corn syrup and the like and after mixing the composition is screened to any predetermined particle sieve size. As an alternative, if preferred, togranulation, the just prepared mixture can be slugged through conventional tablet machines and the slugs comminuted before the fabrication of the tablets. The freshly prepared tablets can be coated or they can be left uncoated. Representative of suitable coatings are the non-toxic coatings including shellac, methylcellulose, carnauba wax, styrenemaleic acid copolymers and the like. For oral administration, compressed tablets containing 0.1 milligram to 5 milligrams calculated as the free acid of the prostaglandins are manufactured in the light of the above disclosure and by art known fabrication techniques well known to the art and set forth in Remingtons Pharmaceutical Science, Chapter 39, Mack Publishing Co., 1965.

The manufacture of capsules for oral use consists essentially of mixing the active compound with a non-toxic carrier and enclosing the mixture in a gelatin sheath. The capsules can be in the art known soft form of a capsule made by enclosing the compound in intimate dispersion within an edible oil or the capsule can be a hard capsule consisting essentially of the novel compound mixed with a non-toxic solid such as talc, calcium stearate, calcium carbonate or the like.

The daily dose administered for the compounds will of coursevary with the particular novel compound employed because of the varying potency of the compounds, the chosen route of administration and the size of the recipient. The dosage administered is not subject to definite bounds, but it will usually be an effective amount of the pharmacologically active free acid form produced upon the metabolic release of the prostaglandin to achieve the biological function of the prostaglandin. Representative of a typical method for administring the putrescine or agmatine prostaglandin compounds is by the injectabletype administration route. By this route, a sterile solution containing the putrescine or agmatine prostaglandin compound is administered intravenously at the rate of 0.01 microgram to 0.15 microgram per minute per kilogram of body weight by means of an infusion pump, at the rate of 10 to 15 milliliters per hour. For example, the compound l-amino 4 guanidobutane 9a,11a,l5(S)-trihydroxy-13- trans-prostenoate can be administered by this route for producing stimulation of smooth muscles. The compound is administered by the injectable route in a form suited for injection, such as mixed with sterile physiological saline, or in aqueous solutions having incorporated therein an agent that delays absorption such as aluminum monostearate and the like.

Suitable topical preparations can easily be prepared by, for example, mixing 500 mg. of the putrescine or agmatine prostaglandin with 15 g. of cetyl alcohol, 1 g. of sodium lauryl sulfate, 40 g. of liquid silicone DC 200 Dow Corning, 43 g. of sterile water, 0.25 g. of methylparaben and 0.15 g. of propylparaben and warming the mixture with constant stirring to about C. and then permitting the preparation to congeal. The preparation can be readily applied to the skin by inunction or it can be applied topically by dispensing the preparation from a conventional surgical gauze dispenser, and the like. Suitable procedures for preparing topical applications are set forth in Remingtons Pharmaceutical Science, Chapter 37, as cited supra.

The compounds of this invention can also be conveniently administered in aerosol dosage form. An aerosol form can be described as a self-contained sprayable product in which the propellant force is supplied by a liquified gas. For administering a self-propelled dosage form of about mg. to 500 mg. that is used about 3 or 4 times daily for inhalation therapy, the bronchodialator 1,4- diaminobutane-11u,15 (S)-dihydroxy 9 oxo5-cis,13- trans-prostadienoate is suspended in an inert non-toxic propellant in a commercially available compressed-gas aerosol container. Suitable propellants include trichloromonofluoromethane, dichlorodifiuromethane, dichlorodifluoroethane, monochlorodifluoroethane and mixtures thereof. The inert gas can be mixed with non-toxic cosolvents such as ethanol, if desired, to produce the aerosol form. If the compound is administered by oral inhalation employing conventional nebulizers, it is convenient to dilute in an aqueous solution about 1 part of the putrescine or agmatine prostaglandin with about 200 to 300 parts of solution, for administering 3 or 4 times per day.

For administering to valuable domestic animals or for administering to laboratory animals for scientific studies, the compound is prepared in the form of a food premix, such as mixing with dried fish meal, oatmeal and the like, and then the prepared premix is added to the regular feed, thereby administering the compound to the domestic or laboratory animal in the form of feed.

The above examples and disclosure are set forth merely for illustrating the mode and the manner of the invention and various modifications and embodiments can be made by those skilled in the art in the light of the invention without departing from the spirit of the invention.

I claim:

1. l-amino 4 guanidobutane :,15 (S)-dihydroxy-9- oxo-l3-trans-prostenoate.

2. l-amino 4 guanidobutane 11u,15(S)-dihydroxy-9- oxo-S-cis, 1 3-trans-prostadienoate.

3. l-amino 4 guanidobutane 9a,11a,15 (S) trihydroxy-13-trans-prostenoate.

4. l-amino 4 guanidobutane bis-(11a,15(S)-dihydroxy-9-oxo-13-trans-prostenoate) 5. l-amino 4 guanidobutane bis-(11a,15(S)-dihy droxy-9-ox0-5-cis,13-trans-prostadienoate) 6. l-amino 4 guanidobutane biS-(8a,11o,l5(S)-trihydroxy-13-trans-prostenoate) 7. l-amino 4 guanidobutane 1101,15 (S)-dihydroxy- 9-oxo-5-cis,13-trans,17-cis-pr0statrienoate.

8. l-amino 4 guam'dobutane 15(S)-hydroxy-9-0x0- 10,l3-trans-prostadienoate.

9. l-amino 4 guanidobutane 15 (S)-hydroxy-9-oxo- 5-cis,10,13-trans-prostatrienoate.

10. l-amino 4 guanidobutane 9p,11a,15(S)-trihydroxy-lB-trans-prostenoate.

11. l-amino 4 guanidobutane 9a,11a,15 (S) trihydroxy-S-cis,13-trans-prostadienoate.

12. l-amino 4 guanidobutane 9p,11a,15 (S) trihydroxy-S-cis,13-trans-prostadienoate.

13. 1 amino 4 guanidobutane 9a,11a,15(S)-trihydroxy-S-cis,13-trans,17-cis-prostatrienoate.

14. 1 amino 4 guanidobutane 9/3,11a,15(S)-trihydr0xy-5-cis,1S-trans-17-cis-prostatrien0ate.

15. l-amino 4 guanidobutane 15(S)-hydroxy-9-oxo- 8 12) ,13-trans-prostadienoate.

16. l-amino 4 guanidobutane 15 (S)-hydroxy-9-oxo- 5-cis-8 12 13-trans-prostatrienoate.

17. l-amino 4 guanidobutane 15(S),19-dihydroxy- 9-0x0-8( 12) 1 S-trans-prostadienoate.

18. l-amino 4 guanidobutane 11a,15(S)-dihydroxy- 9-oxo-prostanoate.

References Cited Mark at al.: Clinical Research, vol. 17, p. 252 (1969).

BERNARD HELFIN, Primary Examiner G. A. SCHWARTZ, Assistant Examiner US. Cl. X.R.

260404, 404.5, 468 D, 488 R, 501.2, 514 D; 424-311, 312, 316, 317, 318 

1. 1-AMINO-4-GUANIDOBUTANE 11A, 15(S)-DIHYDROXYL-9OXO-13-TRANS-PROSTENOATE. 